ABSTRACT Heavy alcohol consumption is widespread among persons living with HIV (PLWH). In PLWH, the gut-associated lymphoid tissues are a site of on-going CD8+ T-cell activation and proliferation. Chronic alcohol intake injures the gut mucosal barrier and predisposes CD8+ T-cells to chronic stimulation by pro-inflammatory microbial products and subsequent transition to an immunosenescent phenotype, a state of geriatric-like decline in immune response to vaccination and carcinogenesis. In a pilot study of PLWH, we have shown that chronic alcohol intake as measured by the Alcohol Use Disorder Identification Test (AUDIT) score was significantly associated with greater numbers of circulating activated-immunosenescent CD8+ T-cells (AIT) (CD3+ CD8+ CD28- CD38+). We have separately shown that aging in humans is linked to gastrointestinal dysbiosis. Alcohol- induced dysbiosis has been suggested to induce gut barrier leak, which may be mediated in part by expression of enzymes, such as catalase-peroxidase (KatG), that convert alcohol to cytotoxic acetaldehyde, a potent inducer of epithelial barrier permeability. It is unknown whether or not dysbiosis, acetaldehyde production, and gut barrier leak contributes to premature CD8+ T-cell activated-immunosenescence in PLWH who consume alcohol. In a preliminary analysis of PLWH who consume alcohol, we found that greater short-term alcohol intake as measured by the 30-day total-grams alcohol timeline followback (TLFB) and serum phosphatidylethanol concentration and medium-term alcohol intake as measured by the AUDIT score, were associated with greater fecal dysbiosis based on 16S rRNA gene deep-sequencing. Furthermore, increased AIT were associated with similar changes in fecal bacterial communities. TLFB, AUDIT, and AIT each positively correlated with the predicted abundance of KatG gene count, suggesting that acetaldehyde-production capacity parallels alcohol- and AIT-associated dysbiosis. We propose to elucidate the mechanisms by which alcohol accelerates CD8+ T- cell activated-immunosenescence development in a cohort of PLWH who drink alcohol. We propose the overarching hypothesis that gut dysbiosis augments AIT through increased gut microbial acetaldehyde production and increased gut barrier leak. This proposal will provide the applicant with integrated training in microbial bioinformatics as well as high-throughput cellular/biomolecular quantitative methodologies to test the hypotheses that increased 1) gut dysbiosis, 2) fecal microbial acetaldehyde production, and 3) gut barrier leak associate with increased AIT in PLWH who consume alcohol. The studies proposed in the applicant?s research training plan will leverage the data being collected within the on-going NIAAA-funded, Aging in Louisiana: Immunosenescence, HIV, and Socioenvironmental Factors (ALIVE) Study to provide a future physician-scientist with vital training in translational research and to link alcohol/HIV-associated co-morbidities to specific bacterial targets that may inform the design of future therapy to alleviate the burden imposed by alcohol on PLWH.